Project Summary With 2.1 million new cases in 2018, and 1.8 million deaths, lung cancer is the most common cancer in the world. Radiation therapy is the standard of care for inoperable non-small cell lung cancer and confers a significant survival benefit. Unfortunately, an important side effect of radiation therapy for cancer is Radiation Induced Lung Injury (RILI) - the direct tissue injury due to DNA damage and free radical injury, as well as the subsequent inflammatory response caused by exposure of the lungs to ionizing radiation. 50-76% of patients undergoing radiation therapy for lung cancer each year develop some form of radiation injury as seen on surveillance imaging. Not only is RILI a significant source of morbidity and mortality, but the lung?s sensitivity to radiation limits the amount of radiation which can be given to treat cancer. RILI can be divided into two phases: 1) Acute pneumonitis (1-6 months post-radiation) causing lung inflammation and edema which may require hospitalization and rarely is fatal. 2) Chronic fibrosis phase (months to years post radiation) during which smoldering inflammation causes fibrotic tissue to replace normal lung tissue and results in significant morbidity. Currently, RILI diagnosis is based on clinical history, symptoms, lung function tests, and chest imaging. RILI is typically a diagnosis of exclusion after recurrent malignancy and infection have been ruled out and rarely may require an invasive lung tissue biopsy to exclude alternative etiologies. At best, we can use the current tools to diagnose the presence of RILI, but we are unable to: 1) accurately quantify the severity and distribution of RILI 2) repeatedly assess disease activity and progression. This proposal aims to addresses these unmet needs through non-invasive molecular imaging of type 1 collagen, which is prevalent in active fibrotic disease such as RILI. We hypothesize that a newly developed positron emission tomography probe, 68Ga-CBP8, targeted to type I collagen, will enable earlier detection and accurate quantification of RILI. We further hypothesize that the use of this new targeted imaging approach will allow to better predict disease progression and thus ultimately help to identify which patients may benefit from early treatment. The affinity and specificity of 68Ga-CPB8 for type 1 collagen are well established and we have clinical experience with this agent in the imaging of idiopathic pulmonary fibrosis. Here, for the first time, we propose to use the agent to image radiation-induced lung injury. The proposal is divided into two phases. First, we aim to establish that 68Ga-CPB8 specifically accumulates in regions of RILI and can be imaged with PET. Subjects that underwent radiation therapy for lung cancer and are known to have RILI will be imaged in this proof-of-concept aim and results will be compared to high-resolution computed tomography (HRTC) images. We will conduct this study under a current IND held at Massachusetts General Hospital. In Phase 2, Collagen Medical will obtain its own IND to conduct a larger study where patients will be scanned prior to radiation therapy than followed up early when conventional HRTC imaging is not accurate. We also aim to demonstrate that PET imaging can predict disease progression after exposure to radiation in the chest area.